Using a Single Irb for Nih-Funded Multisite Trials

As clinical trials evolve, the oversight by Institutional Review Boards (IRBs) has also evolved to meet everexpanding needs for both efficiency and changing regulatory requirements in the protection of human subjects. The most significant regulatory change to occur was the change to the Revised Common Rule Research Provision (45 CFR 46.114(b)) that went into effect on 20 January 2020, requiring all cooperative research subject to the Common Rule to use a single Institutional Review Board (sIRB) to review the research. Since the Common Rule affects all federally funded research, clinical trialists performing multicenter trials using federal grants are now required to use an sIRB instead of individual IRBs at each research site in their trials. For those multicenter trialists, using an sIRB offers efficiencies in time and effort which can aid in bringing trial results to fruition both faster and at a lower cost while still providing protection to human subjects. While commercial sIRBs have been available for many years, sIRBs placed at academic institutions and health care systems are relatively new. They can offer the benefit of lower cost for trialists within an institution, and better overall trial management by having more frequent communication and discussion regarding trial issues as well as improved safety management through aggregate safety review. They can also offer increased speed of research review with cooperative planning between trialist and the sIRB representatives. This session will focus on the use of sIRBs from various perspectives to give the view from an academic sIRB, from end users of both an academic sIRB and a health system IRB, and guidance from a clinical regulatory specialist regarding maintaining a trial master file while using an sIRB. Mr. Jarrod Feld from the University of Iowa will present from his perspective as the External IRB Coordinator at the University of Iowa. Mr. Feld coordinates reliance and compliance for University of Iowa human research studies which use the University of Iowa Institutional Review Board as their sIRB, and studies where Iowa relies on another institutional IRB. Mr. Feld also provides guidance to investigators on using an sIRB. Using his experience, Mr. Feld will outline the nature of reliance agreements, discuss working with a range of local IRBs to develop understanding regarding the reliance program and outline best practices for using an sIRB, and discuss enhanced safety management oversight when using an sIRB for large multisite trial. Ms. Tina Neill-Hudson from the University of Iowa will present from her experience as the sIRB Liaison for both the Acute to Chronic Pain Signature (A2CPS) Consortium, an NIH (National Institutes of Health)- funded multisite observational trial, and the Fibromyalgia and TENS in Physical Therapy Study (FM TIPS) study, an NIH-funded embedded pragmatic clinical trial. Ms. Neill-Hudson works with relying sites on completing the necessary regulatory documents needed for reliance agreements and sIRB approval. Ms. Neill-Hudson will discuss the process for obtaining reliance for institutions who may or may not have local IRB oversight and provide examples of specific steps and procedures for obtaining sIRB approval in a timely manner. Ms. Neill-Hudson will speak to the importance of having an sIRB liaison on the study team and the use of SMART IRB. Ms. Catherine Gladden from MassGeneral Brigham will present on using an sIRB for multicenter NIHfunded trials. Ms. Gladden will discuss the use of a Consortium-level reliance agreement and role of the local IRBs. Ms. Gladden oversees the sIRB liaison team at the Coordinating Center for the NeuroNEXT Network and works with the sIRB and local IRBs to ensure local policies and requirements are followed while maintaining compliance with the sIRB and the NeuroNEXT reliance agreement. Ms. Gladden will be discussing best practices for using an sIRB in a multicenter trial and discuss the experience of using an sIRB in the safety management plan. Ms. Cynthia Diltz from the University of Iowa wi l present on the topic of managing a trial master file while using an sIRB. Ms. Diltz will speak on her experience with electronic trial master files versus hard copy master files, and in using commercial software for trial master file management. Using an electronic trial master file is a necessity in the scheme of using an sIRB to assist sponsors and individual clinical research sites to view Institutional Review Board documents in real time and to provide a single storage location for documentation of Institutional Review Board approvals and activities such as continuing review. This session is timely due to the change to the Common Rule mandating the use of an sIRB for all research subject to the Common Rule, which has the most significant impact on trialists at academic institutions and health care systems. In an era of the need for timely study results for use in addressing urgent public health policy concerns, using an sIRB is becoming a necessity. The speed with which clinical trials need to be managed by an IRB has accelerated during recent public health care crises, notably the COVID-19 pandemic. In addition, it is likely that there will be changes to local IRBs as the norm becomes using an sIRB for any research subject to the Common Rule. Investigators and clinical site staff will require education on the evolution of human subject's protection and research review happening at an sIRB instead of within their local IRBs, and assistance in understanding the process and planning for success will be crucial.

Association of Molnupiravir and Nirmatrelvir-Ritonavir with preventable mortality, hospital admissions and related avoidable healthcare system cost among high-risk patients with mild to moderate COVID-19

Background Real-world data is currently limited on the association between oral antiviral therapy and healthcare system burden in patients with mild-to-moderate COVID-19. This study aims to evaluate the clinical and cost effec-tiveness of Molnupiravir and Nirmatrelvir-ritonavir use in reducing mortality in this population. Methods This is a retrospective cohort study involving 54,355 COVID-19 patients during February 22-March 31,2022 in Hong Kong. Inverse probability of treatment weighting (IPTW) was used to adjust patient characteristics. Our exposure of interest was Molnupiravir/Nirmatrelvir-Ritonavir prescription, with all-cause mortality as the pri-mary outcome. IPTW-adjusted multivariate regressions were used to estimate treatment impact on clinic re -atten-dance and unplanned admissions. Finally, attributed cost and incremental cost-effectiveness ratios (ICER) were estimated. Findings In the outpatient cohort (N = 33,217, 61.1%), 16.1% used Molnupiravir and 13.4% used Nirmatrelvir-Ritona-vir, while in the inpatient cohort (N = 21,138, 38.9%), 3.8% used Molnupiravir and 1.3% used Nirmatrelvir-Ritonavir. IPTW-adjusted Cox model estimated that Molnupiravir (hazard ratio (HR)(95%CI)=0.31 (0.24-0.40), P< 0.0001) and Nirmatrelvir-Ritonavir (HR=0.10 (95%CI 0.05-0.21), P< 0.0001) were significantly associated with a reduced mortality hazard. In the outpatient cohort, both antiviral prescriptions were associated with reduced odds for unplanned hospital admissions (Molnupiravir: odds ratio (OR) =0.72 (0.52-0.98), P=0.039;Nirmatrelvir-Ritonavir: OR=0.37 (0.23-0.60), P<0.0001). Among hospitalised patients, both antiviral prescriptions were associated with sig-nificant reductions in the odds ratios for 28-days readmission (Molnupiravir: OR=0.71 (0.52-0.97), P=0.031;Nirma-trelvir-Ritonavir: OR=0.47 (0.24-0.93), P=0.030). ICERs for death averted for Molnupiravir stood at USD493,345.09 in outpatient settings and USD2,629.08 in inpatient settings. In outpatient settings, Nirmatrelvir-ritonavir cost USD331,105.27 to avert one death, but saved USD5,502.53 to avert one death in comparison with standard care. Interpretation In high-risk patients in Hong Kong with mild-to-moderate COVID-19, Molnupiravir and Nirmatrel-vir-Ritonavir prescriptions were associated with reduced all-cause mortality and significant cost savings.

Relationships Between Gratitude and Mental Health Difficulties During the COVID-19 Pandemic in a Southern Region of the United States

Introduction: The extensive disruptions of the COVID-19 pandemic have led to heightened concerns about mental health sequelae. There has been significant interest in identifying factors associated with psychosocial vulnerability or resilience. Aims: This study examined associations of trait grat-itude with mental health difficulties among community residents in a southern state of the US. Methods: In this cross-sectional online investigation, 543 adults were assessed during an earlier phase of the pandemic, characterized by the reopening of facilities but mounting infection rates. Participants were evaluated using a validated measure of trait gratitude and clinically relevant screening assessments of depression, anxiety, and trauma symptoms. Results: After adjusting for a range of pandemic-associated burdens and sociodemographic factors, multivariable analyses indicated that gratitude was significantly related to diminished levels of depression, anxiety, and trauma. These effects remained significant after additional adjustment for other psychosocial resources (religiousness and perceived support). Conclusions: Findings provide novel information regarding relationships between gratitude and reduced mental health difficulties among community residents during a stressful period early in the pandemic. Results set the stage for longitudinal research. A disposition to identify and appreciate beneficial experiences might contribute to more favorable adaptation to communal crises, and warrants further investigation.

Performance Expectation, Anxiety, and Motivation of Triathletes and Swimmers during Different Lockdowns Stages in Covid-19 Pandemic

Oliveira GT, Meireles A, Hudson TA, Soares ER, Souza HLR, Santos MP, Mauad FO, Nascimento BF, Marocolo M, Ferreira RM. Performance Expectation, Anxiety, and Motivation of Triathletes and Swimmers during Different Lockdowns Stages in Covid-19 Pandemic. JEPonline 2022;25(4):75-83. The purpose of this study was to analyze the levels of anxiety during the COVID-19 pandemic and the motivation to return to training and competitions according to sex, sports experience, and training status before and during the isolation of swimmers and triathletes. We used the structured questionnaires Sports Motivation Scale 2 and the Three-Factor Anxiety Inventory 2, and a semi-structured questionnaire containing questions related to age and sex, in addition to a set of general information about their sports practice, such as the level of experience, the number of training sessions per week, and the competitive level and training sessions before and during restriction. A significant difference was observed in the dimensions of anxiety in public autofocus and autonomic hyperactivity between sex during swimming, intrinsic motivation, and identified between modalities and perceived control between sex and between modalities. In general, there was no association between anxiety and motivation and sports level, modality, and sex of the athletes. © 2022,Journal of Exercise Physiology Online. All Rights Reserved.

The Search for Agreement on Logical Fallacy Annotation of an Infodemic

We evaluate an annotation schema for labeling logical fallacy types, originally developed for a crowd-sourcing annotation paradigm, now using an annotation paradigm of two trained linguist annotators. We apply the schema to a variety of different genres of text relating to the COVID-19 pandemic. Our linguist (as opposed to crowd-sourced) annotation of logical fallacies allows us to evaluate whether the annotation schema category labels are sufficiently clear and non-overlapping for both manual and, later, system assignment. We report inter-annotator agreement results over two annotation phases as well as a preliminary assessment of the corpus for training and testing a machine learning algorithm (Pattern-Exploiting Training) for fallacy detection and recognition. The agreement results and system performance underscore the challenging nature of this annotation task and suggest that the annotation schema and paradigm must be iteratively evaluated and refined in order to arrive at a set of annotation labels that can be reproduced by human annotators and, in turn, provide reliable training data for automatic detection and recognition systems. © European Language Resources Association (ELRA), licensed under CC-BY-NC-4.0.

Using Academic Detailing for Educational Outreach to Reduce Opioid Prescribing Rates

Introduction: The opioid epidemic remains a significant public health problem in the US. More than 70,000 people died of an overdose in 2019;over two-thirds of these deaths involved an opioid. Overdoses involving opioids killed nearly 47,000 people in 2018. Arkansas (AR) is one of the highest opioid prescribing states with a rate of 108.1 prescriptions per 100 persons in 2017 and 102.1 in 2018, nearly double the US average of 51.4. Despite this slight improvement to 93.2 in 2019, only 1 county in AR was below the national average by the CDC calculation. This ongoing research uses educational interventions through an Academic Detailing (AD) Program developed by University of Arkansas for Medical Sciences and provided to rural primary care providers (PCPs) in AR counties with the highest opioid-prescribing rates and opioid-overdose deaths. Our overarching goal of the AD Program was to provide 1:1 in-person, evidence-based education to increase provider's knowledge of opioid safety and to offer alternative multidisciplinary pain care and treatment, while reducing opioid prescribing when possible. Method(s): Our trained pharmacist delivered the AD Program education to 103 PCPs from June 21, 2019 to November 26, 2019 in 16 of 75 counties in AR. The AD Program was concentrated to reach PCPs because this area of practice accounts for the largest source of opioid prescriptions. Using data from the AR Prescription Drug Monitoring Program, counties with the highest rates of opioid prescriptions per capita were identified to receive the AD Program education. The session details, including visit duration, topics discussed, materials provided, PCP receptiveness and concerns, and requests for additional information, were tracked in Research Electronic Data Capture database. Result(s): PCPs were given the opportunity to complete a post-visit survey to evaluate the success of the educational outreach. The majority of surveyed PCPs felt that the AD Program session disseminated useful information for their primary care practice. Of the 30 PCPs who responded to the survey, 22 (73%) implemented changes to their pain management approach as a result. Conclusion(s): Many PCPs reported barriers to acquiring patient resources, including financial limitations, lack of local access to multidisciplinary practitioners, and adequate transportation. PCPs in rural communities struggle to apply the evidence-based, multidisciplinary approach to pain management when access to such treatment disciplines and modalities are limited or nonexistent. In 2020, the COVID-19 pandemic halted in-person visits and the AD Program team modified their methods with alternative correspondence. This AD research will continue through November 2022.

Facilitators and Barriers to Implementation of a Transcutaneous Electrical Nerve Stimulation Intervention in a Pragmatic Clinical Trial

Fibromyalgia TENS in Physical Therapy (PT) Study (FM-TIPS) is testing feasibility and efficacy of Transcutaneous Electrical Nerve Stimulation (TENS). We present our experience for implementing TENS into PT clinics and virtual training to participants on TENS in a pragmatic clinical. FM-TIPS is a pragmatic, cluster-randomized clinical trial examining if the addition of TENS to routine PT improves movement-evoked pain in fibromyalgia (FM). FM patients (n=600) will be enrolled from 35 PT clinics across six Midwest healthcare systems into either a TENS or no-TENS group. All subjects randomized by TENS clinics receive TENS starting on Day 1. The no-TENS clinics start after completion of the primary outcome on Day 60. In the TENS group, Physical therapists (PTs) provide TENS education in person, while in the no-TENS group, study staff provide TENS education virtually. To facilitate implementation, we selected a study-specific TENS unit that provides mixed frequency TENS with intensity as the only adjustable parameter. All PTs were trained in proper use of the TENS unit in-person. While most PTs embraced the addition of TENS, some had not used TENS and had difficulty adapting practice to include TENS. For virtual visits in the no-TENS group, a standardized procedure was developed and completed by study staff PTs. TENS units were shipped to subject's and zoom visits were scheduled at the subject's convenience within a 10-day window. Most subjects completed virtual TENS training and implementation without difficulties. Technology limitations provided a significant barrier for some subjects. Most clinics have adopted and incorporated TENS intervention. Implementing virtual TENS training in a pragmatic trial can be successful for participant intervention. Due to the current COVID-19 pandemic, participants are more aware of the need to complete interventions via virtual mechanisms. Barriers to virtual TENS instruction are often due to internet and device limitations. FM-TIPS work is supported by the National Institutes of Health (NIH) through the NIH HEAL Initiative under award number UG3AR076387 from the National Institute of Arthritis and Musculoskeletal and Skin Diseases. This work also received logistical and technical support from the PRISM Resource Coordinating Center under award number U24AT010961 from the NIH through the NIH HEAL Initiative. The content is solely the responsibility of the authors and does not necessarily represent the official views of the NIH or its HEAL Initiative.

Impact of COVID-19 on a Pragmatic, Cluster Randomized Clinical Trial for Fibromyalgia

Our objective was to present our experience on adapting to the challenges of COVID-19 pandemic on a pragmatic clinical trial. Transcutaneous Electrical Nerve Stimulation (TENS) in Physical Therapy (PT) Study (FM-TIPS) is a pragmatic, cluster-randomized clinical trial examining if the addition of TENS to routine PT improves movement-evoked pain in fibromyalgia (FM). FM patients (n=600) were enrolled from 24 PT clinics (12 PT only, 12 PT with TENS) across five healthcare systems. COVID-19 has significantly impacted PT practice and in-person interactions. In response, all PT clinics saw reduced volumes of patients, some clinics furloughed PTs, and some clinics were permanently closed. This led us to put contracts, reliance agreements, and training of clinics on hold and to seek additional clinics that could fill the gap for those who could no longer participate. It also led to a delay in onboarding healthcare systems and inpatient enrollment. In order to protect the integrity of the study and minimize missing data due to potential restrictions of in-person visits we developed alternative strategies. This includes procedures for home instruction of TENS via telehealth, a plan for bringing on backup clinics, and a plan for training virtually and in-person using personal protective equipment and social distancing. Assessment of primary outcome and questionnaire data were transitioned for the patient to perform at home through a patient-portal with embedded patient-specific videos. We have also set up a phone line for patients to call with additional questions or concerns. The impact of COVID-19 on statistical design and analysis was discussed including a plan for uneven enrollment across clinics and a sub-analysis of data for patients enrolled during or after the pandemic. In conclusion, COVID-19 altered the original study design of this large-pragmatic trial to account for greater flexibility for providers and patients to facilitate continued enrollment. NIH.